tbuckley/cabot-search huggingface dataset:
Abstract 6041: Investigating metabolic dependencies of group 3 medulloblastoma
Authors: Derek Dang, Kyle S. Smith, Pooja Panwalkar, John McKolay, Olamide Animasahun, Abhinav Achreja, Deepak Nagrath, Paul A. Northcott, Sriram Venneti
Journal: Cancer Research (2023)

Abstract Medulloblastomas (MB) are the most common pediatric brain malignancy. Transcriptomic, genomic, and epigenomic insights have stratified these tumors into four distinct subtypes: SHH, WNT, Group 3 and Group 4. Of the four subtypes, Group 3 tumors bear the worst prognosis. Each MB subtype is distinguished by their unique transcriptome profile and epigenetic landscape. Metabolic reprogramming is a hallmark of cancer and allows cells to actively promote the utilization of nutrients to support their uncontrolled proliferation. We identified distinct transcriptional metabolic profiles in medulloblastomas. We found that Group 3 MB show upregulation of key anabolic pathways. We then cross-referenced these data from comprehensive single-cell RNA sequencing profiles of cerebellar developmental niches. We found that Group 3 MB exhibits metabolic signature similar that of early progenitors, rhombic lip progenitors, and cerebellar ventricular zone derivatives. Finally, we identify DLAT, the E2 subunit of the pyruvate dehydrogenase complex, as a uniquely upregulated gene in Group 3 MB. Knockdown of DLAT inhibited tumor growth in-vitro and in-vivo suggesting a potential targets for future therapeutic regimens. Citation Format: Derek Dang, Kyle S. Smith, Pooja Panwalkar, John McKolay, Olamide Animasahun, Abhinav Achreja, Deepak Nagrath, Paul A. Northcott, Sriram Venneti. Investigating metabolic dependencies of group 3 medulloblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6041.
Abstract 4032: Discovery of a potent, selective, and orally available SHP2 inhibitor that can penetrate blood-brain barrier
Authors: Miyeon Kim, Dongsu Kim, Kyeong Jin Yoon, Yeejin Jeon, Dohyun Park, Mijung Lee, Dahye Jeon, Soyeon Jang, Jinhwan Kim, Eunji Kim, Jihoon Park, Victor Hong, Sang Kyun Lim, Sungpil Choi
Journal: Cancer Research (2023)

Abstract Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2/PTPN11) is one of the key signaling proteins in many oncogenic receptor tyrosine kinase (RTK) pathways. It mediates RAS-driven downstream signaling and activates gene expression for tumorigenesis. Importantly, a critical role of SHP2 has been found during the process of temporal adaptation and ERK re-activation after the treatment of RAS/RAF/MEK/ERK inhibitors, which means that SHP2 could be a promising therapeutic target to shut down the oncogenic RAS pathway, especially in combination with RAS/RAF/MEK/ERK inhibitors. Here we present preclinical data of an allosteric small-molecule SHP2 inhibitor that is highly potent, selective, and brain-permeable. In vitro biochemical and cellular assays showed excellent potency against SHP2 protein. In addition, we confirmed exceptional in vivo activity in mouse xenograft models, and demonstrated combination effects with a KRAS G12C inhibitor. Most importantly, the BBB penetration and anti-tumor activity in brain was confirmed both in vitro and in vivo, supporting the great potential in treating brain-metastasized tumors. In summary, we have successfully discovered and developed a potent and blood-brain barrier permeable SHP2 inhibitor that provides a novel therapeutic option for diverse cancers associated in the RAS pathway. Citation Format: Miyeon Kim, Dongsu Kim, Kyeong Jin Yoon, Yeejin Jeon, Dohyun Park, Mijung Lee, Dahye Jeon, Soyeon Jang, Jinhwan Kim, Eunji Kim, Jihoon Park, Victor Hong, Sang Kyun Lim, Sungpil Choi. Discovery of a potent, selective, and orally available SHP2 inhibitor that can penetrate blood-brain barrier. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4032.
Abstract 3062: ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex
Authors: Yen-Nien Liu, Wei-Yu Chen, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Zi-Qing Chen, Wan-Hsin Wang, Yu-Ching Wen
Journal: Cancer Research (2023)

Abstract Conventional treatment of prostate cancer (PCa) uses androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to AR-negative phenotype with neuroendocrine (NE) features on histology, which is associated with metabolic disturbances and poor prognosis. However, the association between the metabolic pathways that regulate mitochondrial function and promote NE differentiation (NED) in PCa remains unclear. Here, we show a regulatory mechanism in PCa pathogenesis whereby overexpression of pyruvate kinase L/R (PKLR) mediates mitochondrial disorder and oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED-related aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to mitochondrial dysfunction and NED in PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT-induced NED. Our findings link ADT resistance-driven metabolic reprogramming to NED of PCa through upregulation of PKLR/MYCN/ROMO1 signaling, and further explored the clinical significance of targeting the nuclear PKLR/MYCN complex and evaluated serum ROMO1 as a potential biomarker for aggressive NE-like PCa. Citation Format: Yen-Nien Liu, Wei-Yu Chen, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Zi-Qing Chen, Wan-Hsin Wang, Yu-Ching Wen. ROMO1 mediates mitochondrial function links to neuroendocrine differentiation of prostate cancer enhancement by the nuclear PKLR/MYCN/MAX complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3062.
Abstract 4684: Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library
Authors: Triparna Sen
Journal: Cancer Research (2023)

Abstract Background: Despite recent treatment advances, malignant pleural mesothelioma (MPM) is an aggressive, recalcitrant malignancy. Currently, the histologic subtype (epithelioid/non-epithelioid/biphasic) is the primary prognostic factor; other potential biomarkers to guide therapeutic strategies remain elusive. Even with multimodality therapies, recurrence is high in early-stage disease. In the unresectable/metastatic setting, there are only two FDA-approved regimens, both in the first-line setting: cisplatin/pemetrexed and ipilimumab/nivolumab. Unfortunately, most who respond to first-line treatment experience disease progression within a year. Therapeutic and diagnostic advances in DPM are hindered by a paucity of well-annotated preclinical models which can faithfully recapitulate the complex genomic interplay of the disease. Methods: We established a library of patient-derived xenografts (PDX) from patients with DPM. We performed multi-omic analyses on available PDX and patient samples to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA-sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into &amp;lt; or ≥ 6 months. Results: The mutational landscapes of PDX models strongly correlated with paired tumor samples. There were some differences in CDKN2A/B mutations and relative enrichment of NF2 with fewer BAP1 alterations, the significance of which is being investigated. When compared by histological subtype, we observed an upregulation of genes involved in NOTCH and EMT signaling in the epithelioid models. Models derived from patients with shorter overall survival or poor response to platinum doublet had higher expression of WNT/β-catenin signaling, hedgehog pathway, and epithelial-mesenchymal transition signaling as well as downregulation of immune-activation pathways, including type I and II interferon signaling and inflammatory response pathways. Conclusions: This library of MPM PDXs, the largest to date, effectively mimics human disease and provides unprecedented insight into the genomic, transcriptomic, and protein landscape of MPM. These PDX models will inform future clinical investigations and provide an important new preclinical resource. Citation Format: Triparna Sen. Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4684.
Abstract 832: Exosome-based hybrid nanosystem for targeted TNBC therapy
Authors: Rohan Joshi, Jana Lampe, Jamboor K. Vishwanatha, Amalendu P. Ranjan
Journal: Cancer Research (2023)

Abstract Treatment of metastatic Triple-Negative Breast Cancer (TNBC) remains a challenge despite an increasing number of newer drugs being approved in recent years. The major challenge for improved treatment outcomes for metastatic cancer originates from the fact that the drugs are unable to reach the targeted site and hence are not able to elicit the desired response. Recently, natural mesenchymal stem cells (MSC) cells and their exosomes have been shown to have tumor-homing properties. By exploiting these homing properties, we propose the development of an exosome-polymeric hybrid nanosystem (EPHN) by using exosomes for their targeting ability to enhance the targetability and thus the therapeutic efficacy of the drug against TNBC. In this study, we bioengineered MSC exosome-coated drug-loaded polymeric nanoparticles to deliver our chemotherapeutic drug in a targeted fashion. To isolate the MSC exosomes, we grew the cells in exosome-free media and used the ultracentrifugation standard method. The MSC exosomes had a size of approximately 70 ± 5 nm and a PDI of 0.3. Our exosome sample was positive for exosomal proteins and negative for all other extracellular vesicles. The optimal doxorubicin-loaded PLGA nanoparticles were prepared using a microfluidics method resulting in a higher entrapment efficiency of 42 ± 3% and a smaller size of 70 ± 3 nm and a PDI of 0.2. To make the exosome-coated NPs, we used the extrusion method. After extrusion, the zeta potential of our EPHN was closer to -11mV compared to PLGA NPs (-50mV), which demonstrates that our NPs were coated with an exosomal membrane. We were able to make MSC exosome-coated drug-loaded polymeric nanoparticles and show that they were stable and uniform in size. Microfluidics-assisted doxorubicin-loaded PLGA nanoparticles show uniform size and higher entrapment efficiency. Release kinetics showed a strong burst phase release over the first 8 hours and subsequent sustained release up to 72 hours. In vivo biodistribution of EPHN shows better tumor accumulation compared to PLGA NP. The next stage in this project is in vivo tumor efficacy testing in breast cancer tumor models. This targeted NP system can serve as a novel therapeutic platform for developing improved treatments for metastatic TNBC. Citation Format: Rohan Joshi, Jana Lampe, Jamboor K. Vishwanatha, Amalendu P. Ranjan. Exosome-based hybrid nanosystem for targeted TNBC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 832.
Abstract 2813: Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment <i>via</i> ECM1
Authors: Fanghui Chen, Yang Fan, Chris Tang, Qin Richard, Zheng Wei, Yong Teng
Journal: Cancer Research (2023)

Abstract Radiotherapy plays an essential role in cancer treatment, yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. PKM2, an enzyme that regulates the final rate-limiting step of glycolysis, has different functions in the occurrence, progression and metastasis of cancer. However, whether PKM2 plays a vital role in radioresistance is unclear, especially in head and neck squamous cell carcinoma (HNSCC). Here we report the upregulation of PKM2 in primary post-radiotherapy tumor tissues collected from radioresistant HNSCC patients. Using multidisciplinary approaches, we found elevated PKM2 in response to radiation, which confers radioresistance in HNSCC cells via extracellular matrix protein 1 (ECM1). Mechanistically, PKM2 activates STAT5 signaling pathway in HNSCC cells upon radiation, which enhances ECM1 expression. Moreover, ECM1 upregulation mediated by PKM2 prevents effector T cells from migrating to radioresistant head and neck tumors. While depletion of ECM1 overcomes PKM2-mediated radioresistance in orthotopic xenograft mice through altering the profile of chemo-attractants, which in turn remodels the tumor microenvironment to promote more cytotoxic T cells home to tumors. These novel and significant findings not only demonstrate a novel mechanism underpinning the interaction between tumor-derived PKM2 and immune cells in radioresistance but also provide a possible therapeutic strategy to overcome the failure of radiotherapy in HNSCC patients. Citation Format: Fanghui Chen, Yang Fan, Chris Tang, Qin Richard, Zheng Wei, Yong Teng. Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2813.
Abstract 574: Depletion of regulatory T cells without interruption of IL-2 signaling by antibody against CD25 for enhancing antitumor immunity
Authors: Yuxuan Gao, Feng He, Hao Peng, Kefei Wu, Hui Zhao, Yanpeng Feng, Feng Hao, Guojin Wu, Jinying Ning
Journal: Cancer Research (2023)

Abstract Depleting regulatory T cells from the tumor microenvironment is an attractive strategy for enhancing immunotherapy. Here we developed a humanized antibody against CD25 (H11E11-2V1) with Treg-biased binding. This antibody has a medium affinity to CD25 (KD=8.9nM), weaker than Daclizumab (KD=1.5nM) and RG6292 (KD=4.5nM). Primary T cells activated with CD3 and CD28 beads had increased CD25 expression. H11E11-2V1 bound to Treg (CD4+Foxp3+) with a concentration as low as 0.07nM, similar to RG6292, while it has no detectable binding to activated Teff (CD4+Foxp3-) with a concentration below 2nM (vs. RG6292 below 0.7nM). In addition, H11E11-2V1 did not block IL-2 signaling in NK-92 cells, which expressed CD25 on the cell surface, while Daclizumab blocked the IL-2 signaling. Daclizumab inhibited T cell proliferation (ki67+%) and activation (Granzyme B+%), but not by RG6292 and H11E11-2V1. In vitro cytotoxicity assay indicated that H11E11-2V1 with modified Fc to enhance ADCC specifically depletes Treg from activated primary T cells at a minimal concentration of 0.07nM (vs. RG6292 at 0.14nM) while leaving 90% of Teff intact. In the in vivo MC38 murine tumor model with mice whose CD25 was replaced with human CD25, H11E11-2V1 given by I.P. injection suppressed tumor growth with higher efficiency than RG6292. These results suggested that H11E11-2V1 was an excellent candidate therapeutical antibody against CD25 for cancer therapy. Citation Format: Yuxuan Gao, Feng He, Hao Peng, Kefei Wu, Hui Zhao, Yanpeng Feng, Feng Hao, Guojin Wu, Jinying Ning. Depletion of regulatory T cells without interruption of IL-2 signaling by antibody against CD25 for enhancing antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 574.
Abstract 6048: OGT/CDK5/ACSS2 axis regulates breast cancer brain metastatic growth
Authors: Emily Esquea, Lorela Ciraku, Giang Le Ming, Mauricio Reginato
Journal: Cancer Research (2023)

Abstract Brain metastases (BMs) in breast cancer patients is considered an end-stage event, with no effective drug treatment and a median survival after diagnosis measured in months. Currently, there are no effective drug treatment for BM patients, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to lack of lipid availability in the brain environment and are highly dependent on fatty acid synthesis for growth and survival. However, the signaling pathways that regulate precursors of fatty acid synthesis and lipid metabolism in breast cancer brain metastatic (BCBM) tumors are not known. Here, we show that BCBM cells can generate acetyl-CoA, a major metabolite feeding lipid biosynthesis, via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinse-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Breast cancer cells selected to metastasize to the brain contain higher levels of O-GlcNAcylation, OGT. and ACSS2-Ser267 phosphorylation compared to parental cells, and we show that human breast cancer brain metastatic patient samples contain elevated ACSS2-Ser-267 levels. Additionally, overexpression of the OGT, CDK5, or ACSS2-S267D phospho-mimetic mutant confers a growth advantage of breast cancer cells in the brain in vivo. Importantly, we show that ACSS2 is required for breast cancer growth in the brain but not in the mammary fat pad. Pharmacologically targeting the CDK5 or ACSS2 with respective small molecule inhibitors reduces tumor growth in orthotopic ex vivo brain slice model. These results suggest a crucial role for OGT/CDK5/ACSS2 signaling axis to regulate lipid metabolism in BCBM cells and identify CDK5 and ACSS2 as novel therapeutic targets for treatment of breast cancer brain metastatic growth. Citation Format: Emily Esquea, Lorela Ciraku, Giang Le Ming, Mauricio Reginato. OGT/CDK5/ACSS2 axis regulates breast cancer brain metastatic growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6048.
Abstract 5198: Humanized mice for preclinical efficacy evaluation of drugs targeting GARP
Authors: Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao
Journal: Cancer Research (2023)

Abstract Introduction: GARP (Glycoprotein-A repetitions predominant) is a cell surface receptor which is coded by Lrrc32 (Leucine rich repeat containing protein 32) and involved in the activation of TGF-beta. The expression of GARP has been widely found in various cells including Treg, activated B cells, mesenchymal stromal cells and many types of cancer cells. In the tumor microenvironment (TME), GARP from Treg promotes the growth of tumor via secretion of immune suppressive TGF-beta. Result: We established GARP humanized mouse model (hGARP) on C57BL/6 background in which the signal peptide and extracellular domain of mouse GARP (mGARP) was replaced by human GARP (hGARP). Similar expression level of hGARP on Treg cells in splenocytes from C57BL/6-hGARP mice was observed compared with mGARP in wildtype mice. After treating with anti-hGARP antibody, tumor growth was inhibited in the cohort engrafted with MC38 colorectal cancer cell line. Flow cytometry analysis of the tumor infiltrating lymphocytes revealed an abundant accumulation of hGARP on the Treg cells suggesting that blocking of hGARP in Treg cells contributed to the therapeutic efficiency. In addition, hGARP expression was also found on platelet cells from C57BL/6-hGARP mice, which is similar to human. After treating with anti-hGARP, we also found a significant reduction of platelet cells in C57BL/6-hGARP mice. In vivo assay suggested that the reduction of platelet cells from C57BL/6-hGARP mice correlated well with the binding of anti-hGARP. Conclusion: C57BL/6-hGARP is a well-established mouse model for the pre-clinical evaluation of both therapeutic effect and toxicity of anti-hGARP therapy. Citation Format: Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. Humanized mice for preclinical efficacy evaluation of drugs targeting GARP. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5198.
Abstract 2999: Hippo signaling pathway regulates cancer-cell-intrinsic MHC-II expression in melanoma
Authors: Shengqing Gu
Journal: Cancer Research (2023)

Abstract MHC-II is known to be mainly expressed on the surface of antigen-presenting cells (APCs). Nevertheless, increasing evidence suggests that MHC-II is also expressed by solid tumor cancer cells and may be associated with better immunotherapy responses. However, the regulation of MHC-II in cancer cells remain unclear. In this study, we leveraged data mining and experimental validation to elucidate the regulation of MHC-II in cancer cells and its role in modulating the response to immunotherapy. We collated an extensive collection of omics data to examine the cancer-cell-intrinsic MHC-II expression and its association with immunotherapy outcomes. We then tested the functional relevance of cancer-cell-intrinsic MHC-II expression using a syngeneic transplantation model. Finally, we performed data mining to identify pathways potentially involved in the regulation of MHC-II expression, and experimentally validated candidate regulators. Comprehensive meta-analysis of multiomics data from an exhaustive collection of data revealed that MHC-II is heterogeneously expressed in various solid tumors, and its expression is particularly high in melanoma. Using a syngeneic transplantation model, we further established that melanoma cells with high MHC-II responded better to anti-PD-1 treatment. Data mining followed by experimental validation revealed the Hippo signaling pathway as a potential regulator of melanoma MHC-II expression. Citation Format: Shengqing Gu. Hippo signaling pathway regulates cancer-cell-intrinsic MHC-II expression in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2999.